Molecular recognition is
central to biology, and high-affinity binding proteins now play an essential
role in the pharmaceutical industry. However, existing protein-based drugs are
mainly based on the engineering of naturally existing proteins or monoclonal
antibodies (mAbs), which are usually quite unstable and can only tolerate a
limited number of modifications; thus therapeutic proteins developed from
natural proteins frequently suffer from poor stability, manufacturability, and
in many cases, significant immunogenicity.
Longxing Cao has developed a
method to design de novo proteins to bind to a specific site on the surface of
a protein using no information other than the three-dimensional structure of
the target.
These de novo proteins do not
ever exist in nature, and they are designed based on basic physical and
chemical principles using computers. The de novo proteins can be precisely
crafted as novel drugs, catalysts, and materials to address the 21st-century
challenges in medicine, energy, and technology.
To demonstrate his work, Longxing Cao and colleagues designed binding
proteins to 12 diverse protein targets with very different shapes and surface
properties. Biophysical characterization shows that the binders are hyperstable
and bind their targets with nanomolar to picomolar affinities, and for the five
proteins that were able to crystallize, the computational models of the bound
complexes closely match the crystal structures. This new method enables the
targeted design of binders to sites of interest on a wide variety of proteins
for diagnostics and therapeutics applications. There are several advantages of
these de novo binders compared to the usual antibodies-based therapies and
diagnostic tools, such as high stability, low cost of expression, and highly
controllable modifications. These de novo mini-protein binders have a great
potential to be used as the next-generation therapeutic drugs and diagnostic
tools.
During the Covid-19 pandemic,
Longxing Cao successfully designed mini protein inhibitors that could bind with
picomolar affinity to the SARS-CoV-2 Spike protein and prevent the virus from
infecting cells.
Unlike neutralizing
antibodies, the de novo inhibitors are designed against the most conserved
region of the virus spike protein without being distracted by immune dominant
epitopes; they retain high potency to the existing pandemic variants and are
most likely to be resilient to future changes. These inhibitors can be
manufactured cheaply and administered directly into the respiratory system as
prophylactics and therapeutics.
